Therapeutic Innovation & Regulatory Science

Since 1962, when the Food and Drug Administration was given broad power to regulate investigations of new drugs, several major regulatory themes have emerged. First, the FDA has sought to protect the rights of human subjects by demanding adequate preclinical safety studies and requiring that investigators obtain subjects' informed consent and give proper consideration to ethical issues. Second, the FDA has sought to ensure the integrity of data produced by clinical trials through recordkeeping requirements and enforcement actions against investigators and sponsors. Finally, the FDA has to some extent involved itself in the scientific merits of proposed research, although the Agency's role in this regard has been controversial. Recent revisions in the FDA regulations governing investigational new drugs are unlikely to make fundamental changes in the Agency's programs.

This article describes an action plan to be followed during an FDA sponsor/monitor inspection. The plan identifies the responsibilities of all individuals who may be involved in the inspection. It also covers rules, policies, and the basic philosophy to be taken during the inspection. The plan consists of three sections—the FDA arrival, the role of the company escort, and the conclusion of the inspection.

The purpose of the Institutional Review Board (IRB), protection of the rights and welfare of human research subjects, is outlined. The written consent form must inform the subjects that determination of safety and efficacy is the purpose of the study. The FDA has not found it necessary to disqualify IRBs, since compliance is achieved by lesser actions, such as temporary suspension of authority to review FDA regulated studies. The FDA does not prohibit preparation of portions of informed consent forms by the sponsor if objectivity and accuracy are scrupulously maintained. Deliberately misleading study subjects could render the consent invalid. The accuracy of written translations of consent forms must be assured by the IRB. Advertising to prospective study subjects should be regarded as the initiation of the informed consent process, and held to the same constraints. Payment for participation in the study must be reviewed by the IRB to assure lack of undue influence. The function of the IRB should be limited to protection of the human subjects of the research.

Because of the multinational nature of the pharmaceutical industry, the methods used to obtain marketing approvals for Glaxo products are most effective when they meet the scientific and ethical requirements of the major markets for which they are targeted. In most instances, the optimal course is to develop universally acceptable data proving the safety and efficacy of the products. The acceptance of Good Laboratory Practices (GLPs) and Good Clinical Practices (GCPs) concepts, as developed by the US Food and Drug Administration, has helped to establish continuity in the conduct and reporting of preclinical and clinical research. As similar regulatory requirements are adopted in Great Britain, Europe, Japan, Scandinavia, and other major markets, Glaxo is challenged to identify and develop appropriate methods and procedures to assure the quality and integrity of research data and submissions. This presentation outlines methods used at Glaxo to assure consistency in research methods and results and compliance with FDA regulatory requirements. These include: shared clinical data bases; consistency in auditing techniques; cross-training of compliance personnel; and experience sharing between quality assurance and compliance groups.

A clinical development program between the American and European arms of a multinational pharmaceutical company can be integrated, shared, or separate. The first two options allow faster development and may facilitate earlier marketing. The basic requirements are an agreed policy across the Atlantic on respective contributions to the corporate clinical trial program, then the harmonization of trial design, data capture, and analysis.

As pharmaceutical research becomes increasingly global in scope, and as the pace of the development process increases, foreign external resources will become more and more critical to these processes. Within the very recent past, several US-based Contract Research Organizations (CROs) have established European operations or have established “joint ventures” with European CROs. Similarly, European CROs have begun to develop US operations. Regardless of whether foreign research is conducted “under the IND” or not, protecting the quality of clinical data is simply good business sense. The first step toward this objective is a careful evaluation of the proposed CRO: abilities, resources, and experience. Experience in conducting IND studies (and finding investigators willing to meet IND regulatory and quality requirements) becomes a critical factor. Special attention needs to be given to such issues as signed v oral informed consent, IRB v Ethics Committee, and review of source documents. Like their US counterparts, foreign CROs frequently promise more than they can provide, and it is best to be aware of that before the contract is signed.

As competition in the pharmaceutical industry continues to increase, quality assurance (QA) management will need to reevaluate the role of their organizations within the corporation. QA units must downplay the traditional “policeman” role and assume a more constructive role. The key to this new role is confirming that data bases meet corporate and regulatory standards and evaluating the sense/nonsense of regulatory submissions for management.

Since the advent of FDA's Bioresearch Monitoring Program, the pharmaceutical industry has carefully reviewed and revised procedures related to the conduct of clinical research. This review process has occurred with vigor over the past 10 years, particularly with regard to the monitoring of clinical studies by sponsor companies. Despite these efforts, problems in clinical research continue and the level of regulatory noncompliance at the sites of clinical investigation appears to remain static.

Over a period of 10 years, Schering has worked with at least 15 contract research organizations (CROs), including everything from IRB review to Phase III long-term safety studies. Perhaps 90% to 95 % of the studies have been “short-term” protocols, ie, Phase I, biopharmaceutical/bioequivalence, dermal irritation or sensitivity studies, etc. These have been the most successful. This article outlines some of the advantages-disadvantages of doing different types of studies and gives some recommendations for increasing the chances of a successful venture for both parties.

The use of clinical data generated outside the United States in US drug registration is becoming more common. In order for the FDA to accept such data, various requirements must be met by the study sponsor and investigators. Difficulties in meeting these requirements often arise in the areas of ethical review, patient informed consent, general record-keeping, and access to clinical records for audit purposes. Clear communication between the sponsor and investigator regarding regulatory requirements is the single most important factor for the success of these studies. Problems that are commonly experienced are identified and practical approaches to these problems are discussed.

The use of clinical research organizations (CROs) has become increasingly common in recent years. Studies conducted by CROs are always expensive and, in almost all instances, important to the contracting company. For these reasons, it is vital that the best CRO be selected for the study at hand. The selection process must be taken very seriously and it should be remembered that the best CRO for one study may not be the best one for another study that differs in size, complexity, and/or therapeutic area. After identifying and screening a number of CROs, the final selection should include input from a number of people. These will come from clinical research, data processing, regulatory affairs, etc depending on the nature of the study. The IND regulations require that contracts be very specific concerning what responsibilities are to be transferred to a CRO. Time frames for completion of major tasks and penalties for noncompliance should be included in contracts. It is suggested that both the CRO and selected clinical investigators be visited periodically during a contracted study to help assure that the study is conducted on schedule and in compliance with applicable regulations.

In 1979 Bristol-Myers Company began conducting investigative audits into non-US trials in an effort to assess the quality, scientific merit, and utility of these studies. Since then, they have conducted approximately 140 on-site clinical audits in 20 countries on 4 continents, and have encountered a great variety of different regulations, languages, customs, and problems. In 1985, an additional European-based audit group was established. Currently, Bristol-Myers Company audits non-US studies with both United States and European audit personnel using the same methodology and a mix of auditing teams.

The United States Food and Drug Administration (FDA) conducts more than 200 inspections of clinical sponsors and investigators each year. The sponsors, monitors, and investigators of every important trial submitted to the FDA in support of a new drug application (NDA) for premarket approval may be inspected. FDA inspections are mostly routine—89% involve no further follow-up by the FDA. However, failed inspections can result in disqualification of the investigator, disqualification of the data, or termination of the investigational new drug exemption (IND) that gives the sponsor the right to conduct the experiments. Moreover, common faults of researchers, such as careless recordkeeping, can cause failure. Generally, the FDA is unlikely to impose extreme sanctions unless adequate case histories of patients are unavailable, records are falsified, or human subjects are put at peril. A sponsor or investigator can be protected during an FDA inspection by knowing a few common sense guidelines that are described in the article.

This article is an introduction to artificial intelligence (AI), especially the place of expert systems (ES) in AI. Some applications of expert systems in other industries are discussed, as well as potential areas of application within the pharmaceutical industry. Advantages and disadvantages of developing ES using so-called AI languages v ES shells are covered. A product review is presented, including AI languages, induction ES shells, straightforward rule shells, and sophisticated ES development environments. Also included is a discussion of the problems and pitfalls that may await anyone attempting to develop ES in pharmaceutical R&D. Finally, some recommendations are offered that they may be useful to those just getting started in this area.

An overview of the drug discovery/drug development process is presented in this article. Areas covered include drug sourcing, screening, preclinical workup, process development, formulation, metabolism and pharmacokinetics, toxicology, clinical development, and postregistrational activity. Also stressed is the importance of communication and Master Plan development.

This article will review the background for concerns regarding consistency in labeling for products marketed in several countries, the pharmaceutical industry's response to those concerns, and will briefly describe a recent Congressional request to the Office of Technology Assessment for a comprehensive study of this subject. Finally, a description will be given of methods used by several multinational companies in achieving labeling consistency on a worldwide basis.